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Supersensitive Genotyping Spots More Mutations in Lopinavir Monotherapy Trial
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
From Jules: there was much discussion here regarding low-level 'minority' mutations. In other words, these are mutations NOT detected by standard genotype resistance tests, but ultrasensitive genotype testing can detect them and several studies have found that the presence of low-level mutations can cause viral failure. At last year's Resistance Workshop two important oral presentations found that patients were significantly more likely to experience viral failure if low-level mutations were found. The question now is can the technology used to detect low-level mutations be translated into clinical care. There were several presentations here that evaluated these tests. Over the next several years these tests will be evaluated and developed and it appears that in several years these testing methods are expected to be available.
People in whom lopinavir/ritonavir maintenance monotherapy failed in the OK04 trial had more protease inhibitor (PI)-related mutations on single-genome sequencing than with the standard genotyping test originally used in the study [1]. Still, mutation rates were low during monotherapy even with the ultrasensitive single-genome test, and the monotherapy group had fewer occult mutations than the triple-therapy maintenance group.
OK04 involved 205 people who controlled viral replication with lopinavir/ritonavir plus two nucleosides and never took a failing regimen [2]. Investigators randomized 102 people to continue their triple regimen and 103 to drop the nucleosides and continue only twice-daily lopinavir/ritonavir.
After 48 weeks of randomized treatment 15 people-11 in the monotherapy group-had a viral load above 500 copies (range 524 to 72,300 copies) and had standard genotyping to search for resistance mutations. Two people in the monotherapy group had a major PI mutation (M46I and M46I, I54V, and V82A), as did 1 in the triple-therapy group (I54V and V82A).
John McKinnon (University of Pittsburgh) and coworkers including OK04 investigators analyzed 517 single-genome sequences from 13 people who had standard genotyping after failure--9 taking only lopinavir/ritonavir and 4 continuing their triple regimen. Two of 9 people in the monotherapy group (22%) had a major PI mutation (M46I and V82A) not uncovered by standard genotyping. Three of 4 people (75%) in the triple-therapy maintenance group had a major PI mutation (M46I) not seen by the standard test. Single-genome sequencing also disclosed several minor PI mutations missed by standard genotyping- L10F, M36I, F53L, V77I, G73C, V82I, and L90V.
The Stanford University resistance algorithm reckoned that newly discovered major and minor mutations decreased viral susceptibility to lopinavir/ritonavir in 4 of the 5 people with new mutations.
McKinnon and colleagues recommended "continued investigation of low-frequency drug-resistant viral variants that emerge during virologic rebound to determine their clinical significance and impact on future treatment regimens."
References
1. McKinnon JE, Delgado R, Arribas JR, Pulido F, Mellors JW. More frequent detection of lopinavir resistance by single genome sequencing at virological failure of lopinavir/ritonavir maintenance therapy in the OK04 study. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 80.
2. Pulido F, Arribas JR, Delgado R, et al. Lopinavir-ritonavir monotherapy versus lopinavir-ritonavir and two nucleosides for maintenance therapy of HIV. AIDS. 2008;22:F1-F9.
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